Project Summary The proposed work addresses a problem highlighted by the NEI Audacious Goals Initiative as ?essential to resolve?: identifying ways to regenerate damaged neurons and promote their reconnection to the correct targets in the central nervous system. In mice, a crushed optic nerve can be regenerated by concurrent manipulation of growth-control pathways and neural activity. Yet these regenerating optic nerves may not form appropriate connections because they grow into an atrophied thalamus whose inputs to cortex are weakened. Thus, functional regeneration requires strengthening of thalamocortical inputs representing the damaged eye to re- establish binocular mapping of visual space onto cortical circuits. Similar challenges are faced in early postnatal development, when a weak incoming input from the ipsilateral eye must match the mapping laid down in a cortex already dominated by the contralateral eye. This proposal examines the circuit mechanisms in primary visual cortex necessary for successful regeneration and integration of weak inputs in primary visual cortex, using in- vivo two-photon microscopy of calcium activity in alert mice and whole-cell slice electrophysiology, and then tests the effectiveness of inducing similar conditions in adulthood. The overall hypothesis is that compartmentalized dendritic activity promotes large-scale integration of new inputs into primary visual cortex. Preliminary data suggest that direct cholinergic input to one class of inhibitory neurons, the regular-spiking, somatostatin- expressing interneurons that inhibit dendrites, is lost as the critical period closes, leading these neurons to shift from compartmentalized dendritic activity to more synchronous activity. Chemogenetic control of somatostatin interneurons will be used to promote dendritic compartmentalization in adult cortex and to test whether this enhances regeneration. These experiments are expected to reveal new mechanisms that explain how the closure of a critical period in visual development reduces the capacity for establishment and strengthening of synaptic connections in cortex. In the long term, this knowledge is likely to promote incorporation of weak inputs onto their appropriate targets during regeneration after injury or disease in adulthood, which would achieve a key goal of the NEI and improve treatment options for vision loss.